US9611284B2 - Prostaglandin-bisphosphonate conjugate compounds, methods of making same, and uses thereof - Google Patents

Prostaglandin-bisphosphonate conjugate compounds, methods of making same, and uses thereof Download PDF

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US9611284B2
US9611284B2 US13/687,762 US201213687762A US9611284B2 US 9611284 B2 US9611284 B2 US 9611284B2 US 201213687762 A US201213687762 A US 201213687762A US 9611284 B2 US9611284 B2 US 9611284B2
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Robert N. Young
Stephen Arns
Anne Moreau
Mohammed Monzur Morshed
Romelo Gibe
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Simon Fraser University
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    • C07F9/5722—
    • C—CHEMISTRY; METALLURGY
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
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    • A—HUMAN NECESSITIES
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/548—Phosphates or phosphonates, e.g. bone-seeking
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
    • C07F9/5721—
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/59—Hydrogenated pyridine rings
    • C07F9/598—
    • C—CHEMISTRY; METALLURGY
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
    • C07F9/65127—
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • the present invention relates to conjugate compounds and methods of making and using same.
  • Prostaglandins are a sub-class of eicosanoids found in most body tissues and implicated in a variety of physiological functions in animals, including smooth muscle contraction, reproduction, autoimmunity, inflammation, reduction of intraocular pressure, etc.
  • Prostaglandin E 2 (PGE 2 ) has been associated with various physiological and/or pathological conditions such as stimulation of bone formation, increase in bone mass, arthritis, pain, inflammation, cancer, multiple sclerosis, etc.
  • PGE 2 binds to four receptors (EP1, EP2, EP3 and EP4).
  • the EP4 receptor is associated with intracellular cyclic adenosine monophosphate (cAMP) production, and is distributed in a wide variety of tissue types suggesting a major role in PGE 2 -mediated biological events, such as smooth muscle relaxation, intraocular pressure, pain (in particular inflammatory, neuropathic and visceral pain), inflammation, neuroprotection, lymphocyte differentiation, bone metabolic processes, allergic activities, promotion of sleep, renal regulation, gastric or enteric mucus secretion and duodenal bicarbonate secretion.
  • cAMP cyclic adenosine monophosphate
  • EP4 agonists include, without limitation, compounds as set forth in, for example, WO 02/24647, WO 02/42268, EP 1132086, EP 855389, EP 1114816, WO 01/46140, WO 01/72268, WO 05/116010, WO 03/047417, or U.S. Pat. No. 7,238,710. Many EP4 agonists have however been associated with systemic side effects.
  • Bisphosphonates are drugs used to strengthen bone and have been implicated in inhibiting bone resorption and bone targeting.
  • Prostaglandin-bisphosphonate conjugate compounds have been described in for example U.S. Pat. No. 5,409,911 or U.S. Pat. No. 6,121,253.
  • the invention provides, in part, conjugate compounds.
  • the invention also provides synthesis methods for making the compounds, and uses of the compounds.
  • the invention provides a compound according to Formula I, or a pharmaceutically acceptable salt thereof:
  • X may be —C—, —S—, —O—, or —NH—; R 2 and R 3 may each independently be —H or halo; Ar may be aryl; W may be —H, —C(O)V, or —C(O)OV; Y may be optionally substituted tetrazole, —C(O)OR 1 , or —C(O)NHSO 2 R′; n may be 1, 2 or 3; V may be optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted heteroalkyl; R 1 may be H or optionally substituted lower alkyl; R′ may be optionally substituted lower alkyl or optionally substituted aryl; and is a double or single bond, and where Y or W is conjugated to a bisphosphonate moiety.
  • the bisphosphonate moiety may be conjugated via a linker.
  • R 1 may be —(CR 5 R 6 )—O—C(O)—O—Ar, wherein Ar may be optionally substituted aryl, R 5 may be H or lower alkyl, and R 6 may be H or lower alkyl.
  • R 1 may be —(CR 5 R 6 )—O—C(O)—NH—(CH 2 ) m —C(PO 3 H 2 ) 2 OH, where R 5 may be H or lower alkyl; R 6 may be H or lower alkyl and m may be 1, 2, 3, 4, 5, or 6.
  • Y is optionally substituted tetrazole and X is CH 2 .
  • n may be 1, 2, 3, 4, 5, or 6; and R 1 may be lower alkyl.
  • R 7 and R 8 may be each independently H, small alkyl, cycloalkyl group or CF 3 ; m may be 1, 2, 3, 4, 5, or 6; and o may be 0, 1, 2, 3, 4, 5, or 6.
  • the invention provides a compound according to Formula IV or V, or a pharmaceutically acceptable salt thereof:
  • X may be —C—, —S—, —O—, or —NH—;
  • R 1 and R 2 may be each independently H, small alkyl, cycloalkyl group or CF 3 ;
  • R 3 may be a electron donating or electron withdrawing group;
  • m may be 1, 2, or 3;
  • n may be 1, 2, 3, or 4; and
  • o may be 1, 2, 3, or 4.
  • the compound may be hydrolysable in vivo. In alternative embodiments, the compound may be inactive prior to hydrolysation and/or may be active subsequent to hydrolysation.
  • the invention provides a composition comprising a compound according to the invention in combination with a carrier.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the invention, in combination with a pharmaceutically acceptable carrier.
  • the invention provides methods of selectively delivering a compound to bone or an associated site, the method comprising administering an effective amount of a compound or composition according to the invention to a subject in need thereof.
  • the associate site comprises a site adjacent to a bone in need of treatment.
  • the bone in need of treatment may be a green stick fracture, compound fracture, lateral fracture, pathologic fracture resulting from an invasive tumor, compression fracture, or a fracture requiring a surgical procedure for realignment of a bone.
  • the invention provides methods of treating or preventing a condition associated with abnormal or excessive bone loss, or with abnormal or reduced bone resorption, or with abnormal calcium metabolism comprising administering an effective amount of a compound or composition according to the invention to a subject in need thereof.
  • the invention provides for the use a compound or composition according to the invention for treating or preventing a condition associated with abnormal or excessive bone loss, or with abnormal or reduced bone resorption, or with abnormal calcium metabolism in a subject in need thereof.
  • the condition may be selected from the group consisting of osteoporosis (such as glucocorticoid-induced osteoporosis), Paget's disease, abnormally increased bone turnover, bone graft, periodontal disease, alveolar bone loss, tooth loss, bone fracture, periprostheticosteolysis, osteogenesisimperfecta, and metastatic bone disease.
  • osteoporosis such as glucocorticoid-induced osteoporosis
  • Paget's disease abnormally increased bone turnover
  • bone graft such as glucocorticoid-induced osteoporosis
  • periodontal disease such as glucocorticoid-induced osteoporosis
  • alveolar bone loss such as glucocorticoid-induced osteoporosis
  • tooth loss such as glucocorticoid-induced osteoporosis
  • osteogenesisimperfecta such as metastatic bone disease.
  • the subject may be a human.
  • the invention provides a method of making a compound according to the invention by providing a EP4 agonist having a C-1 carboxyl group or tetrazoyl moiety, providing a bisphosphonate with a free primary or secondary amino moiety; and conjugating the EP4 agonist and the bisphosphonate.
  • the invention provides a compound made by such a method.
  • the invention provides a method of selectively delivering a conjugate compound to bone or an associated site, by administering an effective amount of a compound according to the invention or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the invention provides a method of treating or preventing a condition associated with abnormal or excessive bone loss, or with abnormal or reduced bone resorption, or with abnormal calcium metabolism comprising administering an effective amount of a conjugate compound according to the invention or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the invention provides for use of an effective amount of a conjugate compound according to the invention or a pharmaceutically acceptable salt thereof for treating or preventing a condition associated with abnormal or excessive bone loss, or with abnormal or reduced bone resorption, or with abnormal calcium metabolism in a subject.
  • FIG. 1 is a graph showing hydrolysis of the conjugate 6 and liberation of 1 in rat plasma at 37° C.
  • FIG. 2 is a graph showing hydrolysis of the conjugate 8.
  • FIG. 3 is a graph showing hydrolysis of the conjugate 56.
  • the invention provides, in part, amino-bisphosphonate conjugated compounds and uses thereof, methods of making same, and intermediates used in the methods of making the compounds.
  • the invention provides derivatized EP4 agonist compounds and uses thereof, methods of making same, and intermediates used in the methods of making the derivatized EP4 agonist compounds.
  • the invention provides novel EP4 agonist-bisphosphonate conjugate compounds and uses thereof, methods of making same, and intermediates used in the methods of making the EP4 agonist-bisphosphonate conjugate compounds.
  • the conjugate compounds provide simultaneous delivery of the bisphosphonate and the agent conjugated to the bisphosphonate to a site of action, such as bone.
  • the EP4 agonist-bisphosphonate conjugate compounds provide simultaneous delivery of the EP4 agonist and the bisphosphonate to a site of action, such as bone.
  • the conjugate compounds are hydrolyzable in vivo to release the bisphosphonate and the agent conjugated to the bisphosphonate.
  • the EP4 agonist-bisphosphonate conjugate compounds are hydrolyzable in vivo to release the EP4 agonist and bisphosphonate components.
  • the conjugate compounds are inactive until hydrolyzed and the bisphosphonate and the agent conjugated to the bisphosphonate are released.
  • EP4 agonist-bisphosphonate conjugate compounds are inactive until hydrolyzed and the EP4 agonist and bisphosphonate components released.
  • the agent conjugated to the bisphosphonate (e.g., an EP4 agonist) and the bisphosphonate are each individually active upon release, as measured by standard procedures for each.
  • release as used herein is meant the liberation of the bisphosphonate and the agent conjugated to the bisphosphonate such as by hydrolysis or enzyme action, from a conjugate compound.
  • release as used herein is meant the liberation of an EP4 agonist moiety and a bisphosphonate moiety, for example, by hydrolysis or enzyme action, from an EP4 agonist-bisphosphonate conjugate compound as described herein.
  • the release may be measured, for example, in blood or plasma, after the conjugate has become bound to bone in vivo, or in any suitable system or assay described herein or known in the art.
  • the release may take a period of time, for example, about 1 day to about 30 days, or any value or set of values between this range, for example, about 7 days to about 14 days, such as about 7, 8, 9, 10, 11, 12, 13, or 14 days.
  • the release may differ from in plasma and from bone. Accordingly, in some embodiments, a conjugate compound that is stable or exhibits slow release in plasma would be useful in that it would allow for binding to bone prior to release of the individual components.
  • the ability of the conjugate compound to be targeted to bone and to be released from it may be the determinative characteristic.
  • the EP4 agonist or other agent-bisphosphonate conjugate compounds may be delivered directly to bone.
  • the EP4 agonist or other agent-bisphosphonate conjugate compounds reduce the systemic side effects associated with EP4 agonists or other agents.
  • the EP4 agonist or other agent-bisphosphonate conjugate compounds may be administered at lower doses compared to each of the individual components.
  • the EP4 agonist-bisphosphonate conjugate compounds combine bone growth stimulating EP4 receptor selective agonists and bone resorption inhibiting amino-bisphosphonates in bone targeting pro-drugs which, on systemic administration, bind to bone and enzymatically liberate both of the two components in situ slowly over time thus avoiding or reducing the systemic side effects associated with EP4 agonists.
  • the conjugate compounds according to the invention are hydrolyzed at a rate that allows for dosing once a week.
  • the actions of the EP4 agonist or other agent and the bisphosphonate may be additive or synergistic.
  • the invention provides methods to directly couple tetrazoles with primary or secondary amines to provide dual pro-drugs which, when hydrolyzed, release the two components intact.
  • the invention provides methods to directly couple the tetrazole moieties of, for example, an EP4 agonist or other agent, with primary or secondary amines to provide dual pro-drugs which, when hydrolyzed, release the two components intact.
  • the invention provides methods to directly couple the carboxylic acid moieties of, for example, an EP4 agonist or other agent, with primary or secondary amines to provide dual pro-drugs which, when hydrolyzed, release the two components intact.
  • the invention provides methods to directly couple the alcohol moieties of, for example, EP4 agonists or other agents, with primary or secondary amines to provide dual pro-drugs which, when hydrolyzed, release the two components intact.
  • bisphosphonate as used herein is meant an amino-bisphosphonate compound. Any known bisphosphonate which has an secondary or primary amine functionality capable of coupling to an EP4 agonist or other agent and which targets in vivo to bone may be used, whether or not that particular bisphosphonate has bone resorption inhibiting activity or is useful in the treatment of a disorder as described herein.
  • bisphosphonates may have the following general structure, where m may be 1, 2, 3, 4, 5 or 6.
  • a “bisphosphonate moiety” as used herein is the portion of a bisphosphonate that is conjugated via the amino group to another compound, such as an EP4 agonist or other agent.
  • conjugated is meant the linkage of a bisphosphonate and an agent conjugated to the bisphosphonate, generally via a linker such as those described herein or known in the art. In general, the linkage is releasable and occurs in situ after binding of the conjugated compound to bone.
  • Bisphosphonates include, without limitation, alendronic acid, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid; alendronate (also known as alendronate sodium or alendronate monosodium trihydrate), 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium trihydrate; alendronic acid and alendronate are described in U.S. Pat. No. 4,922,007, to Kieczykowski et al., issued May 1, 1990; U.S. Pat. No. 5,019,651, to Kieczykowski et al., issued May 28, 1991; U.S. Pat. No. 5,510,517, to Dauer et al., issued Apr. 23, 1996; U.S.
  • EP4 agonists include, without limitation, compounds containing a carboxyl or tetrazole group or an alcohol group, as set forth in, for example, WO 02/24647, WO 02/42268, EP 1132086, EP 855389, EP 1114816, WO 01/46140, WO 01/72268, etc.
  • EP4 agonists having a hydroxyl group at position 15, or a carboxylic acid or tetrazole group at position 1 may be reacted with an amino bisphosphonate as described herein.
  • EP4 agonists include compounds 1 and 2 and examples of clinically active bisphosphonates (BPs) include alendronate/alendronic acid (3), pamidronate (4) or neridronate (5).
  • BPs clinically active bisphosphonates
  • compounds according to the invention include a compound according to Formula I, or a pharmaceutically acceptable salt thereof:
  • R 1 may be —(CR 5 R 6 )—O—C(O)—O—Ar, where Ar may be optionally substituted aryl, R 5 may be H or lower alkyl, R 6 may be H or lower alkyl.
  • R 1 may be —(CR 5 R 6 )—O—C(O)—NH—(CH 2 ) m —C(PO 3 H 2 ) 2 OH, where R 5 may be H or lower alkyl; R 6 may be H or lower alkyl; m may be 1, 2, 3, 4, 5, or 6.
  • Y is optionally substituted tetrazole and X is CH 2 .
  • the C1-C7 chain group may include a double bond, for example, at the C5-C6 position and may be cis or trans.
  • the C1-C7 chain group may include a heteroatom, such as O or S or as described herein.
  • a compound according to Formula I specifically excludes compound 8:
  • compounds according to the invention include a compound according to Formula II, or a pharmaceutically acceptable salt thereof:
  • R 3 are F, and Ar is phenyl, X may be —S—, —O—, or —NH—; n may be 2 or 3; and m may be 1, 2, 4, 5 or 6.
  • a compound according to Formula II specifically excludes compound 8:
  • compounds according to the invention include a compound according to Formula III, or a pharmaceutically acceptable salt thereof:
  • compounds according to the invention include a compound according to Formula IV or Formula V, or a pharmaceutically acceptable salt thereof:
  • Alkyl refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing no unsaturation and including, for example, from one to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, the alkyl group may be optionally substituted by one or more substituents as described herein. Unless stated otherwise specifically herein, it is understood that the substitution can occur on any carbon of the alkyl group.
  • straight or branched chain alkyl groups include, but are not limited to, methyl, trifluoromethyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, 1-heptyl, or 1-octyl.
  • ring structure is meant a cycloalkyl, aryl, heteroaryl, or any cyclic structure that may be optionally substituted.
  • Aryl refers to a monocylic or bicycled ring structure wherein all rings are aromatic and are formed of carbon atoms, for example, phenyl or naphthyl groups. Unless stated otherwise specifically herein, the term “aryl” is meant to include aryl groups optionally substituted by one or more substituents as described herein. Accordingly, in some embodiments, the term “aryl” may refer to heteroaryl with, for example, rings of 5 or 6 or more atoms containing one or two heteroatoms such as N, S, or O.
  • Halo refers to halogen groups such as bromo, chloro, fluoro, iodo, etc. In some embodiments, suitable halogens include fluorine.
  • any group described herein may be substituted or unsubstituted.
  • a group may be substituted with any desired substituent or substituents such as one or more of the following group: H, alkyl (C 1-10 ), alkenyl (C 2-10 ), alkynyl (C 2-10 ), aryl (5-12 members), arylalkyl, arylalkenyl, or arylalkynyl, each of which may optionally contain one or more heteroatoms selected from O, S, P, N, F, Cl, Br, I, or B, and each of which may be further substituted, for example, by ⁇ O; or optionally substituted forms of acyl, arylacyl, alkyl-alkenyl-, alkynyl- or arylsulfonyl and forms thereof which contain heteroatoms in the alkyl, alkenyl, alkynyl or aryl moieties; halogen (e.g., chloro, iodo
  • substituent groups include benzyloxy; O-alkyl; O-aryl; aryl; aryl-lower alkyl, etc.
  • a substituted group may have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 substituent groups. These substituent groups may optionally be further substituted with a substituent as listed herein. Substituents may also be optionally substituted by a bridge structure, for example —OC(O)O— or —OC(O)NH—. In some embodiments, substituents are not further substituted.
  • “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • “optionally substituted alkyl” means that the alkyl group may or may not be substituted and that the description includes both substituted alkyl groups and alkyl groups having no substitution. Examples of optionally substituted alkyl groups include, without limitation, methyl, ethyl, propyl, etc.
  • “optionally substituted tetrazole” means that the tetrazole group may or may not be substituted and the description includes both substituted tetrazoles and tetrazoles having no substitution.
  • Compounds may be in acid, base, or salt form.
  • the term “compound” or “compounds” refers to the compounds and conjugates discussed herein and includes precursors, intermediates, and derivatives of the compounds, including acyl-protected derivatives, and pharmaceutically acceptable salts of the compounds, precursors, and derivatives.
  • the invention also includes prodrugs of the compounds, pharmaceutical compositions including the compounds and a pharmaceutically acceptable carrier, and pharmaceutical compositions including prodrugs of the compounds and a pharmaceutically acceptable carrier.
  • all of the compounds of the invention contain at least one chiral center.
  • the compounds of the invention can have one or more chiral centers and/or double bonds.
  • the formulations, preparation, and compositions including compounds according to the invention can include mixtures of stereoisomers, individual stereoisomers, and enantiomeric mixtures, mixtures of multiple stereoisomers, double-bond isomers (i.e., geometric E/Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or ( ⁇ )) or cis/trans isomers).
  • the chemical structures depicted herein, and therefore the compounds of the invention encompass all of the corresponding stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, e.g., racemates.
  • the compound may be supplied in any desired degree of chiral purity.
  • Enantiomeric and stereoisomeric mixtures of compounds of the invention can typically be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Enantiomers and stereoisomers can also be obtained from stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
  • EP4 agonist-bisphosphonate conjugates may be prepared as described herein or elsewhere. It is to be understood that modifications of the methods and schemes as described herein, when performed using standard techniques or achieved by routine experimentation, are encompassed herein.
  • suitable conjugates may be prepared, for example, by linking the tetrazole, carboxylic acid or hydroxyl moiety of a compound (e.g., an anti-neoplastic agent) using bisphosphonate with a free primary or secondary amino moiety using the techniques described herein or modifications thereof.
  • a compound e.g., an anti-neoplastic agent
  • a compound according to Formula I may be prepared by:
  • suitable conjugates may be prepared, for example, by:
  • R is H or lower alkyl.
  • carbamate conjugates e.g., compound F
  • compound F may be prepared as set forth in Scheme I.
  • the EP4 agonist of general structure EP4a is reacted with a halo-carbonyloxyaryl compound such as A in the presence of a non-nucleophilic base such as diisoproplyethylamineto give the adduct E.
  • E is then reacted with an aminoalkylbisphosphonate such as B, generally in the form of its mono-tetrabutylammonium salt in a solvent such as anhydrous DMF in the presence of an excess of non-nucleophilic base to provide the conjugate F.
  • EWG Electrode Withdrawing group e.g. 4-NO 2 , 2,4-diNO 2 , F, etc.;
  • X may be C, NH, S or O;
  • n may be 1, 2, or 3;
  • m may be 1, 2, 3, 4, 5, or 6;
  • Ar is aryl;
  • R 1 may be lower alkyl or H;
  • R 2 may be H or F;
  • R 3 may be H or F. It is to be understood that, for “m” the chain length is not critical to the synthesis and that any suitable chain length may be used.
  • phenol-acid conjugates (e.g., compound 12) may be prepared as set forth in Scheme II.
  • the EP4 agonist of general structure EP4b is reacted with a protected hydroxyarylalkylcarbonylchloride such as C (or other reactive form of the corresponding carboxylic acid) in the presence of a non-nucleophilic base to provide the intermediate 13.
  • the protecting group R′ is removed to provide 14 and the 14 is reacted with A in the presence of an excess of non-nucleophilic base to provide the conjugate 15.
  • 15 is then reacted with an aminoalkylbisphosphonate such as B, generally in the form of its mono-tetrabutylammonium salt in a solvent such as anhydrous DMF in the presence of an excess of non-nucleophilic base to provide the protected conjugate 12a.
  • EWG Electrode Withdrawing group e.g., 4-NO 2 , 2,4-diNO 2 , F, etc.
  • X may be C, NH, S or O
  • n may be 1, 2 or 3
  • m may be 1, 2, 3, 4, 5 or 6
  • o may be 0, 1, 2, 3, 4, 5, or 6
  • Ar is aryl
  • Z may be COOR 1 , tetrazole, or N-trityl-tetrazole
  • R 1 may be H or lower alkyl
  • R 2 may be H or F
  • R 3 may be H or F
  • R′ may be H or a protecting group. It is to be understood that, for “m” the chain length is not critical to the synthesis and that any suitable chain length may be used.
  • through-acid conjugates e.g., compound 21
  • through-acid conjugates may be prepared as set forth in Scheme III.
  • the EP4 agonist of general formula EP4a is protected on the free hydroxyl group with a suitable removable protecting group PG and the group R 1 is removed and the resulting free carboxylic acid is then reacted with a haloalkyloxycarbonyloxyaryl compound such as D with catalysis with non-nucleophilic base, where the carboxylic acid is first converted to the mercury salt or the silver salt to provide the intermediate 19.
  • the protecting group PG is removed to give 20 and then 20 is reacted with an aminoalkylbisphosphonate such as B, generally in the form of its mono-tetrabutylammonium salt in a solvent such as anhydrous DMF in the presence of an excess of non-nucleophilic base to provide the conjugate 21.
  • EWG Electrode Withdrawing group e.g. 4-NO 2 , 2,4-diNO 2 , F, etc.;
  • X may be C, NH, S or O;
  • n may be 1, 2 or 3;
  • m may be 1, 2, 3, 4, 5, or 6;
  • Ar is aryl;
  • R 1 may be lower alkyl or H;
  • R 2 may be H or F;
  • R 3 may be H or F;
  • R 4 may be H or PG, where PG may be selected from a variety of removable protecting groups known in the art;
  • R 5 may be lower alkyl;
  • R 6 may be H or lower alkyl;
  • Y may be halogen. It is to be understood that, for “m” the chain length is not critical to the synthesis and that any suitable chain length may be used.
  • conjugates according to the invention include those set forth in Table II.
  • conjugates according to the invention include those set forth in Table III.
  • conjugates according to the invention include those set forth in Table IV.
  • Compounds 77 to 80 include the free carboxylic acid forms (i.e., COOH instead of COOEt).
  • Compounds 76 to 85 may be synthesized as described herein.
  • Compounds 76 to 80 may be synthesized as described herein with respect to Compound 8, or Compounds 81 to 85 may be synthesized as described herein with respect to Compound 56.
  • intermediates for use in preparation of conjugates may be prepared as set forth in Scheme VII.
  • Compounds according to the invention include the conjugate compounds described herein, as well as intermediates used in the preparation of such compounds, together with derivatives, salts or stereoisomers thereof.
  • certain compounds e.g., Compound 8 are specifically excluded from one or more of the compounds, compositions, methods or uses according to the invention.
  • the invention provides for conjugation of other agents containing a tetrazole, carboxylic acid or hydroxyl moiety to an amino-bisphosphonate.
  • agents containing a tetrazole, carboxylic acid or hydroxyl moiety may be conjugated to an amino-bisphosphonate.
  • a variety of conditions or disorders in humans and other mammals involve or are associated with abnormal or excessive bone loss, or with abnormal or reduced bone resorption, or with abnormal calcium metabolism.
  • Such conditions or disorders include, but are not limited to, osteoporosis, which may include low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture, glucocorticoid-induced osteoporosis, Paget's disease, abnormally increased bone turnover, bone graft, periodontal disease, alveolar bone loss, tooth loss, bone fractures, periprostheticosteolysis, osteogenesisimperfecta, metastatic bone disease, etc.
  • the conjugate compounds may be used to treat or prevent conditions or disorders associated with abnormal or excessive bone loss, or with abnormal or reduced bone resorption, or with abnormal calcium metabolism, or may be used to treat any condition or disorder that would benefit from targeting a therapeutic agent to the bone.
  • the invention provides methods of enhancing or elevating levels of bone stimulation or inhibiting bone resorption in animal subjects, such as, veterinary and human subjects. This elevation or inhibition can be useful for the prevention or treatment of conditions or disorders associated with abnormal or excessive bone loss, or with abnormal or reduced bone resorption, or with abnormal calcium metabolism.
  • the effectiveness of the compounds in prevention or treatment of conditions or disorders associated with abnormal or excessive bone loss, or with abnormal or reduced bone resorption, or with abnormal calcium metabolism may be confirmed by testing the ability of the compounds to enhance or elevate bone stimulation or inhibit bone resorption using standard techniques.
  • the conjugates may be evaluated first for in vitro for stability in plasma and then in normal animals (e.g., rats) for selective uptake into bones and slow release of the two components.
  • suitable conjugate(s) e.g., rats
  • optimized compound(s) may be evaluated in animal models of osteoporosis or for example in an in vitro model of osteogenesis, i.e., neonatal rat calvaria cell cultures.
  • the compounds may be used in for example in vivo or other assays to show efficacy and tolerability suitable for further development as novel therapies for treatment of disorders and conditions as described herein or found in the art.
  • the methods of the invention are effected by administering a conjugate compound according to the invention to a subject in need thereof, or by contacting a cell or a sample with a compound according to the invention, for example, a pharmaceutical composition comprising a therapeutically effective amount of the compound.
  • compositions including the conjugate compounds according to the invention, or for use according to the invention are contemplated as being within the scope of the invention.
  • pharmaceutical compositions including an effective amount of a conjugate compound as described herein are provided.
  • the conjugate compounds according to the invention target bone or a site at which bone growth stimulation or inhibition of bone resorption is required.
  • a site includes both the area adjacent to a section of bone or group of bones in need of treatment in a subject in need thereof or a region inside the bone, including the site of a fracture or opening which occurs naturally or is intentionally made in the bone or group of bones.
  • Bones in need of treatment may include green stick fractures, compound fractures, lateral fractures, pathologic fractures resulting from invasive tumors, compression fractures and fractures that require surgical procedures for realignment of bones.
  • conjugate compounds and their pharmaceutically acceptable salts, stereoisomers, solvates, and derivatives are useful because they have pharmacological activity in animals, including humans.
  • the conjugate compounds according to the invention are stable in plasma, when administered to a subject.
  • conjugate compounds according to the invention may be provided in combination with any other active agents or pharmaceutical compositions where such combined therapy is useful to treat or prevent conditions or disorders associated with abnormal or excessive bone loss, or with abnormal or reduced bone resorption, or with abnormal calcium metabolism, for example, to treat any condition or disorder described herein or that would benefit from targeting a therapeutic agent to the bone.
  • conjugate compounds according to the invention may be provided in combination with one or more agents useful in the prevention or treatment of conditions or disorders associated with abnormal or excessive bone loss, or with abnormal or reduced bone resorption, or with abnormal calcium metabolism to treat any condition or disorder described herein or that would benefit from targeting a therapeutic agent to the bone.
  • Combinations of conjugate compounds according to the invention, or for use according to the invention, and other therapies useful in the prevention or treatment of conditions or disorders associated with abnormal or excessive bone loss, abnormal or reduced bone resorption, abnormal calcium metabolism, cancer, or any disorder associated with bone or that would benefit from targeting a therapeutic agent to the bone, may be administered separately or in conjunction.
  • the administration of one agent or conjugate compound may be prior to, concurrent to, or subsequent to the administration of other agent(s) or conjugate compounds.
  • the conjugate compounds according to the invention may themselves be considered “prodrugs,” the conjugate compounds may be supplied as further prodrug or protected forms, which release the compound after administration to a subject.
  • the compound may carry a protective group which is split off by hydrolysis in body fluids, e.g., in the bloodstream, thus releasing the active compound or is oxidized or reduced in body fluids to release the compound.
  • a “prodrug” is meant to indicate a compound that may be converted under physiological conditions (e.g., enzymatically) or by solvolysis to a biologically active compound of the invention.
  • the term “prodrug” refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention.
  • Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a subject.
  • prodrug is also meant to include any covalently bonded carriers which release the active compound of the invention in vivo when such prodrug is administered to a subject.
  • Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention.
  • Prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and acetamide, formamide, and benzamide derivatives of amine functional groups in the compounds of the invention and the like.
  • prodrugs may be found in “Smith and Williams' Introduction to the Principles of Drug Design,” H. J. Smith, Wright, Second Edition, London (1988); Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam); The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic Press, 1996); A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113 191 (Harwood Academic Publishers, 1991); Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14; or in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, all of which are incorporated in full by reference herein.
  • Suitable prodrug forms of the compounds of the invention include embodiments in which one of the hydroxyl groups is substituted with C(O)OR, where R is optionally substituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl.
  • R is optionally substituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl.
  • the ester groups may be hydrolyzed in vivo (e.g. in bodily fluids), releasing the active compounds.
  • Conjugate compounds according to the invention can be provided alone or in combination with other compounds in the presence of a liposome, an adjuvant, or any pharmaceutically acceptable carrier, diluent or excipient, in a form suitable for administration to a subject such as a mammal, for example, humans, cattle, sheep, etc. If desired, treatment with a compound according to the invention may be combined with more traditional and existing therapies for the therapeutic indications described herein.
  • Compounds according to the invention may be provided chronically or intermittently. “Chronic” administration refers to administration of the compound(s) in a continuous mode as opposed to an acute mode, so as to maintain the initial therapeutic effect (activity) for an extended period of time.
  • Intermittent administration is treatment that is not consecutively done without interruption, but rather is cyclic in nature.
  • administration should be understood to mean providing a compound of the invention to the subject in need of treatment.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved, for example, by the United States Food and Drug Administration or other governmental agency as being acceptable for use in humans or domestic animals.
  • compositions in accordance with this invention may comprise a salt of such a compound, preferably a physiologically acceptable salt, which are known in the art.
  • pharmaceutically acceptable salt as used herein means an active ingredient comprising conjugate compounds used in the form of a salt thereof, particularly where the salt form confers on the active ingredient improved pharmacokinetic properties as compared to the free form of the active ingredient or other previously disclosed salt form.
  • a “pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a “pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • a “pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
  • the term “pharmaceutically acceptable salt” encompasses all acceptable salts including but not limited to acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartarate, mesylate, borate, methylbromide, bromide, methylnitrite, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutame, a
  • Pharmaceutically acceptable salts of the compounds of the present invention can be used as a dosage for modifying solubility or hydrolysis characteristics, or can be used in sustained release or prodrug formulations.
  • pharmaceutically acceptable salts of the compounds of this invention may include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N′-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.
  • compositions will typically include one or more carriers acceptable for the mode of administration of the preparation, be it by injection, inhalation, topical administration, lavage, or other modes suitable for the selected treatment.
  • Suitable carriers are those known in the art for use in such modes of administration.
  • Suitable pharmaceutical compositions may be formulated by means known in the art and their mode of administration and dose determined by the skilled practitioner.
  • a compound may be dissolved in sterile water or saline or a pharmaceutically acceptable vehicle used for administration of non-water soluble compounds such as those used for vitamin K.
  • the compound may be administered in a tablet, capsule or dissolved in liquid form.
  • the table or capsule may be enteric coated, or in a formulation for sustained release.
  • Many suitable formulations are known, including, polymeric or protein microparticles encapsulating a compound to be released, ointments, gels, hydrogels, or solutions which can be used topically or locally to administer a compound.
  • a sustained release patch or implant may be employed to provide release over a prolonged period of time.
  • Many techniques known to skilled practitioners are described in Remington: the Science & Practice of Pharmacy by Alfonso Gennaro, 20 th ed., Williams & Wilkins, (2000).
  • Formulations for parenteral administration may, for example, contain excipients, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes.
  • Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds.
  • Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.
  • conjugate compounds or pharmaceutical compositions according to the present invention may be administered by oral or non-oral, e.g., intramuscular, intraperitoneal, intravenous, intracisternal injection or infusion, subcutaneous injection, transdermal or transmucosal routes.
  • conjugate compounds or pharmaceutical compositions in accordance with this invention or for use in this invention may be administered by means of a medical device or appliance such as an implant, graft, prosthesis, stent, etc.
  • Implants may be devised which are intended to contain and release such compounds or compositions.
  • An example would be an implant made of a polymeric material adapted to release the conjugate compound, or its individual components, over a period of time.
  • conjugate compounds may be administered alone or as a mixture with a pharmaceutically acceptable carrier e.g., as solid formulations such as tablets, capsules, granules, powders, etc.; liquid formulations such as syrups, injections, etc.; injections, drops, suppositories, pessaries.
  • a pharmaceutically acceptable carrier e.g., as solid formulations such as tablets, capsules, granules, powders, etc.; liquid formulations such as syrups, injections, etc.; injections, drops, suppositories, pessaries.
  • conjugate compounds or pharmaceutical compositions in accordance with this invention or for use in this invention may be administered by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • the conjugate compounds of the invention may be used to treat animals, including mice, rats, horses, cattle, sheep, dogs, cats, and monkeys. However, compounds of the invention can also be used in other organisms, such as avian species (e.g., chickens). The compounds of the invention may also be effective for use in humans.
  • the term “subject” or alternatively referred to herein as “patient” is intended to be referred to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • the conjugate compounds, methods and pharmaceutical compositions of the present invention may be used in the treatment of animals.
  • a “subject” may be a human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc.
  • the subject may be suspected of having or at risk for having a condition or disorder associated with abnormal or excessive bone loss, or with abnormal or reduced bone resorption, or with abnormal calcium metabolism, a cancer, a disorder associated with bone, or a disorder that would benefit from targeting a therapeutic agent to the bone.
  • an “effective amount” of a compound according to the invention includes a therapeutically effective amount or a prophylactically effective amount.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as inhibition of bone resorption, stimulation of bone growth, or treatment of any condition described herein.
  • a therapeutically effective amount of a compound may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual.
  • Dosage regimens may be adjusted to provide the optimum therapeutic response.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects.
  • a “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as inhibition of bone resorption, stimulation of bone growth, or prevention of any condition described herein.
  • a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount may be less than a therapeutically effective amount.
  • a suitable range for therapeutically or prophylactically effective amounts of a compound may be any value from 0.1 nM-0.1M, 0.1 nM-0.05M, 0.05 nM-15 ⁇ M or 0.01 nM-10 ⁇ M.
  • an appropriate dosage level in the treatment or prevention of conditions which require modulation of bone growth or resorption or calcium metabolism, will generally be about 0.01 to 1000 mg per kg subject body weight per day, and can be administered in singe or multiple doses. In some embodiments, the dosage level will be about 0.1 to about 250 mg/kg per day. It will be understood that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound used, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the patient undergoing therapy.
  • dosage values may vary with the severity of the condition to be alleviated.
  • specific dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
  • Dosage ranges set forth herein are exemplary only and do not limit the dosage ranges that may be selected by medical practitioners.
  • the amount of active compound(s) in the composition may vary according to factors such as the disease state, age, sex, and weight of the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • compounds of the invention should be used without causing substantial toxicity, and as described herein, the compounds exhibit a suitable safety profile for therapeutic use.
  • Toxicity of the compounds of the invention can be determined using standard techniques, for example, by testing in cell cultures or experimental animals and determining the therapeutic index, i.e., the ratio between the LD50 (the dose lethal to 50% of the population) and the LD100 (the dose lethal to 100% of the population). In some circumstances however, such as in severe disease conditions, it may be necessary to administer substantial excesses of the compositions.
  • the conjugate compounds according to the invention are hydrolyzed at a rate that allows for dosage once a week.
  • 3a was found to be freely soluble in anhydrous DMF and a variety of other solvents such as dioxane, ethanol and even dichloromethane, allowing for more careful control of the coupling reaction.
  • 3a reacted smoothly with 26a in anhydrous DMF in the presence of 4-5 equivalents of a non-nucleophilic base, di-isopropylethylamine to provide the desired model conjugate 16 in excellent yield (Scheme 2).
  • EP4 receptor agonist tetrazole 1 was reacted with silver triflate and then with D2a to provide the intermediates 22 and 23 in reasonable yields.
  • the mercury salt of 1 formed by exchange with mercuric acetate
  • 22 and/or 23 were then reacted with 3a in DMF to provide the target conjugates 6 and 7 as tetra-n-butylammonium salts.
  • the conjugates were purified by ion exchange (to exchange the tetra-n-butylammonium ion for a proton) and thence by reverse phase chromatography to give 6 and 7 in excellent yields (Scheme 4).
  • the conjugates 6 and 7 required synthesis of activated intermediates (such as 22 and 23) followed by reaction with alendronic acid (3). No such compounds were known in the literature and the reaction of intermediates such as 22 or 23 with 3a was considered to be particularly challenging due to the poor solubility of alendronic acid (3) in any solvent other than water. Thus, while it is possible to use alendronic acid (3) in the conjugation reaction, compound 3a yielded better results.
  • the product D1 was isolated by flash column chromatography (Gediya, Lalji K.; Khandelwal, Aakanksha; Patel, Jyoti; Belosay, Aashvini; Sabnis, Gauri; Mehta, Jhalak; Purushottamachar, Puranik; Njar, Vincent C. O. “Design, Synthesis, and Evaluation of Novel Mutual Prodrugs (Hybrid Drugs) of All-trans-Retinoic Acid and HistoneDeacetylase Inhibitors with Enhanced Anticancer Activities in Breast and Prostate Cancer Cells in Vitro” J. Med. Chem. 2008, 51, 3895-3904).
  • the stability of the conjugates 6 and 7 were evaluated both chemically and in vitro in rat plasma. As the bone in vivo efficacy studies will be done in rats it was desirable to determine if the compounds are sufficiently stable to survive in the blood stream long enough to be taken up into bone via binding of the 1-hydroxy-1,1-bisphosphonate moiety. Treatment of 6 with 1N NaOH led to complete hydrolysis and liberation of 1 (and also 3) within 10 minutes. A mixture of 6 and 7 were incubated in fresh rat plasma at 37° C. and the stability of the conjugate was monitored by appearance of 1 by LC/MS/MS. The conjugate was quite stable but smooth but slow liberation of 1 was observed over 96 hours (see FIG. 1 ).
  • Preparation of the conjugate 8 required the synthesis of the EP4-selective agonist 2.
  • This 11 step synthesis was carried out on large scale starting from (+)-D-pyroglutamic acid to provide 2 and its ethyl ester (2a) (about 2 gm combined total). The synthesis was carried out largely as described in the literature (Y. Han et al. U.S. Pat. No. 7,109,223 B2 Sep. 19, 2006) but with some improvements in the final diastereoselective reduction of the ketone to avoid over-reduction. 2a was reacted with chlorocarbonyloxy-p-nitrobenzene (A1) to provide the reactive carbonate 24 in excellent yield.
  • A1 chlorocarbonyloxy-p-nitrobenzene
  • the conjugate 8 was incubated at room temperature with 0.1 N NaOH during 24 hours to hydrolyze the ethyl ester essentially quantitatively but the carbamate coupling was not hydrolyzed.
  • Conjugate 8 was incubated at 37° C. in fresh rat plasma and the incubation was followed over time by LC/MS/MS monitoring for appearance of 2 ( FIG. 2 ). After 96 hours no significant liberation of 2 was observed indicating that this conjugate is stable in the blood.
  • radiolabelled 2 To evaluate this conjugate in vivo, we prepared radiolabelled 2. We decided that reduction of the ketone penultimate precursor of 2a with a tritiide reagent might be a facile method.
  • the mixture of radiolabelled 6 and 7 and, separately, radiolabelled 8 is diluted with unlabelled compound as required and then dosed to rats (2 or 3 each) by intravenous administration in water at doses of 5 mg/kg. Tolerability is confirmed and blood samples are withdrawn at various time points and disappearance of both label and conjugate from the blood monitored over about 4 hrs by HPLC with in-line scintillation counting.
  • rats are dosed in a similar manner and at various time points after dosing (4 hr, 1 day, 3 days, 7 days) (2-3 rats per time point) rats are sacrificed and long bones dissected, cleaned, dried and weighed before pyrolyzing in a tissue burner with the liberated water trapped and counting in a scintillation counter. This determines the initial uptake at 4 hrs after dosing and the subsequent release of tritiated 1 or 2 from the bone. Scale-up of the conjugates are initiated to allow a 28 day efficacy study in osteopenic female rats.
  • a Hydroxyphenylacetic Acid C15 Hydroxyl Conjugate was synthesized as follows.
  • Carboxylic acid 50 (O. Brummer, T. Z. Hoffman, D.-W. Chen, K. D. Janda. Chem. Comm. 2001, 19-20) (1.0 eq) was dissolved in DMF and treated with DCC (1.1 eq) and pentafluorophenol (1.2 eq). The mixture was stirred at room temperature for 18 h, after which the precipitate was removed by suction filtration and the solvent was removed under reduced pressure. The product was isolated by filtration through a short pad of silica using 5% ethyl acetate/hexanes as the eluting solvent to afford compound 51 as a colorless liquid.
  • Alcohol 52 (1.0 eq) was dissolved in THF and treated with NaH (60% in oil, 1.0 eq). After 10 minutes, pentafluorophenyl ester 51 (1.0 eq) was added as a solution in THF and the mixture was stirred at room temperature for 3 hours. The reaction was quenched by the addition of NH 4 Cl (saturated, aqueous). The layers were separated and the aqueous phase was extracted with diethyl ether (3 ⁇ ). The organic layers were combined, dried over MgSO 4 , filtered and concentrated and the product was isolated by flash chromatography to afford compound 53 as a colorless oil.
  • Silyl ether 53 (1.0 eq) was dissolved in THF and treated with TBAF (1.0 M in THF, 2.0 eq). After stirring at room temperature for 2 hours the reaction was quenched by the addition of NH 4 Cl (saturated, aqueous). The layers were separated and the aqueous phase was extracted with diethyl ether (3 ⁇ ). The organic layers were combined, dried over MgSO 4 , filtered and concentrated and the product was isolated by flash chromatography to afford compound 54 as a yellow oil.
  • Phenol 54 (1.0 eq) was dissolved in dichloromethane and treated with Et 3 N (3.0 eq) and 4-nitrophenylchloroformate (1.1 eq). After stirring at room temperature for 2 hours the reaction was quenched by the addition of NH 4 Cl (saturated, aqueous). The layers were separated and the aqueous phase was extracted with dichloromethane (3 ⁇ ). The organic layers were combined, washed with H 2 O and brine, dried over MgSO 4 , filtered and concentrated. The crude product was filtered quickly through a short pad of silica gel and the product 55 was used directly in the next step without further manipulation.
  • Carbonate 55 (1.0 eq) was dissolved in 1,4-dioxane. To this was added a solution of alendronic acid (1.25 eq) and Et 3 N (6.0 eq) in water, immediately generating a yellow color. After 2.5 hours the reaction was diluted with H 2 O and the layers were separated. The aqueous phase was extracted with dichloromethane (3 ⁇ ), then it was freeze dried to give a waxy yellow solid. The product was isolated by C18 reverse phase flash chromatography using gradient elution from H 2 O to MeOH, affording compound 56 as a white solid.
  • the conjugate was administered intravenously to female Sprague-Dawley rats at 10 mg/kg. Triplicate sets of rats were euthanized at 6 h, 48 h, 168 h and 336 h and tritium levels in bone was measured by incineration of the long bones in a biological oxidizer. After an initial 6 h uptake of 5.9%, 1.4% of the initial dose remained after 14 days.
  • trioxane (0.1086 g, 1.21 mmol) (previously dissolved in 5 mL CH 2 Cl 2 ) to the reaction mixture. Slowly the green color disappeared and formed a light yellow color solution. After 2 hrs added 10 mL saturated NaHCO 3 solution to stop the reaction. Then performed an extraction and collected the organic layer. Dried the organic layer with Na 2 SO 4 . Then performed a hexanes-EtOAc gradient column chromatography to isolate the product 62.

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Publication number Priority date Publication date Assignee Title
US10400000B2 (en) 2015-06-12 2019-09-03 Simon Fraser University Amide-linked EP4 agonist-bisphosphonate compounds and uses thereof
US11312737B2 (en) 2015-06-12 2022-04-26 Simon Fraser University Amide-linked EP4 agonist-bisphosphonate compounds and uses thereof

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